Magnetic field-induced ER stress reprograms the tumor microenvironment to improve triple-negative breast cancer survival

Abstract

BackgroundNon-invasive electromagnetic field (EMF)-based therapies offer a potential route to modulate local tumor-immune interactions but their mechanistic basis remains poorly defined. MethodsWe evaluated Asha therapy, a proprietary low-intensity (50khz, 2 mT, 25% duty cycle) alternating magnetic-field treatment in preclinical breast cancer models. Cellular responses in human triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) were evaluated using bulk RNA sequencing, quantitative proteomics, flow cytometry, and cytokine analysis and proteomics analysis. Tumor microenvironment responses in mouse 4T1 breast cancer model was characterized using single-cell CITE-seq analysis. Functional efficacy was assessed in vivo using the murine 4T1 triple-negative breast cancer model, both as monotherapy and in combination with anti-PD1 checkpoint blockade. Clinical relevance was assessed by deriving a 19-gene neutrophil activation signature from Asha-induced transcriptional changes and projecting it onto two independent TNBC patient cohorts (METABRIC n=338, SCAN-B n=874) for survival analysis. ResultsAsha therapy induced endoplasmic reticulum (ER) stress and activated an adaptive unfolded-protein response in tumor cells, triggering robust NF-{kappa}B and interferon signaling and time-dependent secretion of inflammatory cytokines. In vivo, these tumor-intrinsic changes propagated to the tumor microenvironment (TME), reprogramming fibroblasts from contractile states to immune-recruiting, interferon-responsive phenotypes and enriching for interferon-stimulated, metabolically active neutrophils and macrophages. These coordinated innate immune changes occurred without overt cytotoxicity and were associated with significant reductions in metastasis and improved survival. Combination with anti-PD1 therapy markedly enhanced efficacy, reducing lung metastasis and mortality by 88% compared with control. The neutrophil activation signature derived from Asha-treated tumors was associated with improved overall survival in both METABRIC (log-rank p=0.036) and SCAN-B (p=0.048) TNBC cohorts by Kaplan-Meier analysis, with pooled multivariable Cox regression confirming significant survival benefit (HR=0.75, 95% CI 0.59-0.94, p=0.01). ConclusionsAsha therapy triggers a controlled ER stress response in tumor cells that drives interferon-mediated cytokine release and immune reprogramming of the TME, resulting in anti-metastatic and survival benefits. These findings identify electromagnetic-field exposure as a potential non-pharmacologic strategy to activate innate immunity and sensitize tumors to checkpoint blockade, supporting further clinical development of EMF-based immunotherapy.